The overall goal of this K23 proposal is to train Christopher Vinnard, MD, MPH, MSCE for a career as an independent investigator in HIV research, with a specific emphasis on the treatment and outcomes of HIV- associated tuberculosis (TB). The career development plan includes training in pharmacometrics, an interdisciplinary field that combines expertise in quantitative clinical pharmacology, systems biology, statistics, computing, and non-parametric mathematics. There will be formal mentoring by Dr. Jeffrey Jacobson and Dr. Tawanda Gumbo at UT Southwestern, an expert in anti-TB pharmacology. Drexel University College of Medicine offers a remarkably rich environment, with access to collaborators, educational resources, and facilities that will foster Dr. Vinnard's professional development. Research will focus on the interaction between HIV infection and the absorption of rifampicin, a key anti-TB drug. The goals of this proposal are to provide the candidate with a comprehensive mentoring and didactic program to facilitate independence as a clinical researcher, and to elucidate the role of intrinsic gut dysfunction in rifampicin malabsorption among HIV-infected patients. Specific Aim 1 is to define the relationship of intrinsic gut dysfunction with rifampicin absorption, by linking pharmacokinetic studies with measures of intestinal function, barrier integrity, and systemic immune activation. This project will be performed as a sub-study of the funded R21 Immune Activation and Isoniazid Metabolism in HIV/TB (PI: Bisson), which will enroll HIV/TB patients in Gaborone, Botswana. Specific Aim 2 is to investigate the effect of antiretroviral therapy on the recovery (if any) of rifampicin absorptive capacity. If antiretroviral therapy does not lead to significant improvements in rifampicin absorption, future investigations would evaluate novel adjunctive therapies aimed at optimizing the gut's absorptive function. This project will be performed in the clinical researc facilities of the Division of Infectious Diseases & HIV Medicine at DUCOM, providing Dr. Vinnard with the training experience of leading a longitudinal pharmacokinetic study of anti-TB therapies within his home institution. After the completion of this project, the candidate will be well traind as an independent investigator with expertise as a pharmacometrician. Given the scope of the proposal, the discovery of novel mechanisms for the regulation of rifampicin absorption in HIV-infected patients will provide the foundation for future investigations that will transition Dr. Vinnard from the mentored to the independent phase of this 5-year career development award. Dr. Vinnard also will continue to build his international collaborations during the course of this award period, with guidance from Dr. Jacobson and Dr. Gumbo, including continued collaboration with Dr. Bisson and the UPenn Botswana program. These studies of anti-TB therapies in HIV-infected patients have the potential to transform the treatment of HIV/TB patients throughout the world.